Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An isolated perfused lung model was developed in which the mechanisms of regulation of sensory neuropeptide overflow and bronchoconstrictor responses evoked by antidromic vagal nerve stimulation or various irritants could be studied. For further comparison, non-adrenergic non-cholinergic (NANC) bronchoconstriction was also studied in guinea-pig isolated bronchus and in vivo. In the isolated guinea-pig lung, spontaneous strong postmortem bronchoconstriction occurred; this had to be overcome by the beta 2-adrenoceptor agonist terbutaline. Vagal stimulation, capsaicin, resiniferatoxin (RTX), nicotine, and pH 5 buffer all caused sensory peptide release and bronchoconstriction via a capsaicin-sensitive mechanism. Bradykinin and histamine also stimulated sensory peptide release but evoked bronchoconstriction mainly via capsaicin-resistant mechanisms. Stimulation at low frequency (1 Hz) caused similar degree of sensory nerve activation (peptide release in perfused lung and NANC bronchial contraction in bronchus) as stimulation at 10 Hz. Dactinomycin and the non-peptide SR 48968 selectively blocked the bronchoconstriction induced by neurokinin 2 (NK2) receptor agonists and also depressed that induced either by vagal stimulation or capsaicin, with no prejunctional effect on the overflow of calcitonin gene-related peptide (CGRP). Furthermore, SR 48968 inhibited the bronchoconstriction to citric acid aerosol. The NK1 antagonist CP 96345 had only marginal effects on NANC bronchoconstriction. Tetrodotoxin (TTX) and omega-conotoxin (CTX) inhibited neuropeptide release and bronchoconstriction caused by vagal stimulation or a low concentration of capsaicin but only marginally attenuated the effects evoked by a high concentration of capsaicin, or nicotine. Prejunctional alpha 2-adrenoceptor or opiate receptor activation inhibited the neuropeptide release and bronchoconstriction induced by vagal stimulation or a low concentration of capsaicin. Ruthenium red had a selective inhibitory effect on the overflow of neuropeptides [CGRP, neurokinin A (NKA)] and bronchoconstriction induced by capsaicin and its analogue RTX but not on responses induced by vagal stimulation, nicotine, bradykinin and histamine. It also inhibited CGRP and NKA release and bronchoconstriction caused by pH 5 buffer in lung, as well as cough and nasal irritation provoked by citric acid in vivo. The capsaicin receptor antagonist capsazepine inhibited peptide (CGRP, NKA) release and bronchoconstriction produced by capsaicin but not that evoked by vagal stimulation, nicotine and bradykinin, suggesting selectivity. Citric acid (in vivo) and pH 5 buffer (in vitro) produced bronchoconstriction via activation of capsaicin-sensitive sensory nerves. Interestingly, capsazepine also markedly depressed peptide overflow and bronchoconstriction caused by pH 5 buffer in isolated guinea-pig lung.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction. 769 42

Cough is initiated by activation of afferent nerve fibers with rapidly adapting receptors (RAR) that conduct action potentials in the Adelta range. In addition, various stimuli that activate airway unmylenated C-fibres evoke cough reflexes. We have used a vagally innervated, larynx-trachea-bronchus preparation, isolated from guinea pigs, to study the pharmacology of RARs and C-fibres in vitro. In this preparation afferent fibres with the RAR phenotype are exquisitely sensitive to mechanical perturbation of their receptive fields, but are unaffected by a variety of mediators (e.g. prostaglandins, histamine, bradykinin, serotonin) and by capsaicin. By contrast, C-fibres are much less sensitive to mechanical stimulation, but can be activated by capsaicin and bradykinin. Preliminary evidence supports the hypothesis that bradykinin activate C-fibre by stimulating the capsaicin (vanilloid) receptor VR1. Acids activate both C-fibres and RARs. Acids stimulate RAR fibres by a mechanism that is rapidly inactivated. C-fibres are stimulated by both a rapidly inactivating mechanism, as well as a slowly inactivating mechanism. Drugs that block VR1 inhibit the latter mechanism. Airway inflammation substantially increases the mechanical sensitivity of RAR fibres without affecting their adaptive properties. Airway inflammation also causes a phenotypic switch in neuropeptide innervation of the airways that RAR neurons begin to synthesis neurokinins and calcitonin gene related peptide. In non-inflamed animals these peptides are expressed only in C-fibre neurons. Thus, airway inflammation may not only increase the sensitivity of cough fibres, but may also qualitatively change the role played by sensory neuropeptides in cough reflexes.
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PMID:Physiology and plasticity of putative cough fibres in the Guinea pig. 1209 67

1. Endogenous neuronal lipid mediator anandamide, which can be synthesized in the lung, is a ligand of both cannabinoid (CB) and vanilloid receptors (VR). The tussigenic effect of anandamide has not been studied. The current study was designed to test the direct tussigenic effect of anandamide in conscious guinea-pigs, and its effect on VR1 receptor function in isolated primary guinea-pig nodose ganglia neurons. 2. Anandamide (0.3-3 mg.ml(-1)), when given by aerosol, induced cough in conscious guinea-pigs in a concentration dependent manner. When guinea-pigs were pretreated with capsazepine, a VR1 antagonist, the anandamide-induced cough was significantly inhibited. Pretreatment with CB1 (SR 141716A) and CB2 (SR 144528) antagonists had no effect on anandamide-induced cough. These results indicate that anandamide-induced cough is mediated through the activation of VR1 receptors. 3. Anandamide (10-100 micro M) increased intracellular Ca(2+) concentration estimated by Fluo-4 fluorescence change in isolated guinea-pig nodose ganglia cells. The anandamide-induced Ca(2+) response was inhibited by two different VR1 antagonists: capsazepine (1 micro M) and iodo-resiniferatoxin (I-RTX, 0.1 micro M), indicating that anandamide-induced Ca(2+) response was through VR1 channel activation. In contrast, the CB1 (SR 141716A, 1 micro M) and CB2 (SR 144528, 0.1 micro M) receptor antagonists had no effect on Ca(2+) response to anandamide. 4. In conclusion, these results provide evidence that anandamide activates native vanilloid receptors in isolated guinea-pig nodose ganglia cells and induces cough through activation of VR1 receptors.
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PMID:Anandamide induces cough in conscious guinea-pigs through VR1 receptors. 1241 14

Evidence is presented to support the proposal that activation of the type 1 vanilloid receptor (VR1) is an important sensory mechanism in cough.
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PMID:Cough. 5: The type 1 vanilloid receptor: a sensory receptor for cough. 1498 66

Before a tussive stimulus in the airways can evoke a cough reflex it must first cause action potential discharge in cough-associated vagal sensory nerves. This is initiated by the stimulus first interacting with the receptors and ion channels in the terminal membrane of the sensory fiber in a manner that leads to membrane depolarization. If the stimulus-induced membrane depolarization, referred to as a generator potential, is of sufficient magnitude, action potentials are elicited that are then conducted to the central nervous system. If the action potentials are of sufficient number and frequency, a cough is evoked. The most common tussive stimuli include mechanical perturbations, anosmotic solutions, acidic solutions, and various chemical agents. The mechanisms underlying the transduction of most of these tussive stimuli into a generator potential are only partially understood. In general terms, chemical stimuli interact directly with receptors that are classified as either ligand gated ion channels or metabotropic receptors (e.g. G-protein coupled receptors). Ligand gated receptors are those in which the receptor protein also serves as the ion channel. The metabotropic receptors indirectly modulate the ion channels activity via various signal transduction schemes. Mechanical stimuli are thought to interact with mechanically gated ion channels, and acid can interact with acid sensing ion channels in addition to the capsaicin receptor TRPV1. In this overview some of the specific receptors and ion channels involved in the tussive stimulus-induced generator potentials in vagal afferent nerve terminals are discussed.
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PMID:Sensory transduction in cough-associated nerves. 1644 2

The transient receptor potential vanilloid 1 (TRPV1) is an excitatory cation channel, rather selectively expressed in a subpopulation of nociceptive, primary sensory neurons that promote neurogenic inflammation via neuropeptide release. TRPV1 is activated by noxious temperature, low extracellular pH and diverse lipid derivatives, and is uniquely sensitive to vanilloid molecules, including capsaicin. TRPV1 expression and sensitivity is highly regulated by diverse G protein-coupled and tyrosine kinase receptors. Other exogenous or endogenous chemical agents, including reactive oxygen species, ethanol and hydrogen sulphide sensitize/activate TRPV1. In the airways, TRPV1 agonists cause cough, bronchoconstriction, microvascular leakage, hyperreactivity and hypersecretion. Patients with asthma and chronic obstructive pulmonary disease are more sensitive to the tussive effect of TRPV1 agonists and TRPV1 activation may contribute to respiratory symptoms caused by acidic media present in the airways during asthma exacerbation, gastroesophageal reflux induced asthma or in other conditions. TRPV1 antagonists may be useful in the treatment of these diseases.
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PMID:The transient receptor potential vanilloid 1: role in airway inflammation and disease. 1646 49

A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.
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PMID:Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs. 1662 74

Capsaicinoids are botanical irritants present in chili peppers. Chili pepper extracts and capsaicinoids are common dietary constituents and important pharmaceutical agents. Use of these substances in modern consumer products and medicinal preparations occurs worldwide. Capsaicinoids are the principals of pepper spray self-defense weapons and several over-the-counter pain treatments as well as the active component of many dietary supplements. Capsaicinoids interact with the capsaicin receptor (a.k.a., VR1 or TRPV1) to produce acute pain and cough as well as long-term analgesia. Capsaicinoids are also toxic to many cells via TRPV1-dependent and independent mechanisms. Chemical modifications to capsaicinoids by P450 enzymes decreases their potency at TRPV1 and reduces the pharmacological and toxicological phenomena associated with TRPV1 stimulation. Metabolism of capsaicinoids by P450 enzymes also produces reactive electrophiles capable of modifying biological macromolecules. This review highlights data describing specific mechanisms by which P450 enzymes convert the capsaicinoids to novel products and explores the relationship between capsaicinoid metabolism and its effects on capsaicinoid pharmacology and toxicology.
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PMID:Metabolism of capsaicinoids by P450 enzymes: a review of recent findings on reaction mechanisms, bio-activation, and detoxification processes. 1714 96

A wealth of literature describes the approaches that investigators have used to develop animal models of cough. The relevance of the models to cough in man and disease is still unknown. Furthermore, the choice of animal model that is used will depend on the purpose of the investigation and what questions are being asked. Cigarette smoke is known to cause COPD and cough is a principle symptom where patients demonstrate an increased cough response to citric acid or capsaicin. This paper describes the development of exacerbated cough to these agents in the guinea-pig following cigarette smoke exposure and pharmacological profiling of these models. Male Dunkin-Hartley guinea-pigs were exposed to air or cigarette smoke (4 or 5 research cigarettes daily for the capsaicin and citric acid studies, respectively) for a 3 s puff every 30 s, for up to 10 days. At selected time points conscious, unrestrained animals were placed in a plethysmograph chamber and challenged with an aerosol of 0.3 M citric acid (10 min) or 10 microM capsaicin (7 min). Cough and Penh area under the curve (AUC) were recorded during the exposure and for a further 10 min (citric acid) or 8 min (capsaicin) after exposure. Compounds were administered on day 3 or 11 for citric acid or capsaicin, respectively. Significant enhancement of citric acid-induced cough was evident 24 h (12+/-2 to 24+/-4* coughs) after a single exposure and further enhanced after 2 days (13+/-3 to 36+/-4* coughs). Enhanced cough to capsaicin was not reliable until after 10 days of cigarette smoke exposure (2+/-1 to 14+/-3** coughs). Data are expressed as mean+/-s.e.mean (n=10), *p<0.05, **p<0.01 vs. air-exposed animals (Mann-Whitney rank-sum test). The minimum effective doses to inhibit citric acid-induced cough were 10, 10, 3 and 0.3 mg/kg for codeine (p.o. -30 min), a selective NK(1)/NK(2) antagonist, DNK333 (p.o. -2 h), terbutaline (s.c. -1 h) and atropine (s.c. -1 h), respectively. The minimum effective doses to inhibit capsaicin-induced cough were 3, 1, 0.3 and 0.3 mg/kg for codeine, DNK333, terbutaline (p.o. -2 h) and atropine, respectively. The VR1 antagonists capsazepine and iodo-resiniferatoxin (IRTX) did not inhibit cough in either model. Differences in sensitivity between citric acid and capsaicin to pharmacological agents may be partly explained by the difference in magnitude of response to these agents. Clinically used compounds such as codeine and terbutaline have shown activity in both models, however the relevance of the models to cough in man and disease for potential new therapies is unknown.
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PMID:Animal models of cough: literature review and presentation of a novel cigarette smoke-enhanced cough model in the guinea-pig. 1724 Jan 78

Capsicum-derived ingredients function as skin-conditioning agents--miscellaneous, external analgesics, flavoring agents, or fragrance components in cosmetics. These ingredients are used in 19 cosmetic products at concentrations as high as 5%. Cosmetic-grade material may be extracted using hexane, ethanol, or vegetable oil and contain the full range of phytocompounds that are found in the Capsicum annuum or Capsicum frutescens plant (aka red chiles), including Capsaicin. Aflatoxin and N-nitroso compounds (N-nitrosodimethylamine and N-nitrosopyrrolidine) have been detected as contaminants. The ultraviolet (UV) absorption spectrum for Capsicum Annuum Fruit Extract indicates a small peak at approximately 275 nm, and a gradual increase in absorbance, beginning at approximately 400 nm. Capsicum and paprika are generally recognized as safe by the U.S. Food and Drug Administration for use in food. Hexane, chloroform, and ethyl acetate extracts of Capsicum Frutescens Fruit at 200 mg/kg resulted in death of all mice. In a short-term inhalation toxicity study using rats, no difference was found between vehicle control and a 7% Capsicum Oleoresin solution. In a 4-week feeding study, red chilli (Capsicum annuum) in the diet at concentrations up to 10% was relatively nontoxic in groups of male mice. In an 8-week feeding study using rats, intestinal exfoliation, cytoplasmic fatty vacuolation and centrilobular necrosis of hepatocytes, and aggregation of lymphocytes in the portal areas were seen at 10% Capsicum Frutescens Fruit, but not 2%. Rats fed 0.5 g/kg day-1 crude Capsicum Fruit Extract for 60 days exhibited no significant gross pathology at necropsy, but slight hyperemia of the liver and reddening of the gastric mucosa were observed. Weanling rats fed basal diets supplemented with whole red pepper at concentrations up to 5.0% for up to 8 weeks had no pathology of the large intestines, livers, and kidneys, but destruction of the taste buds and keratinization and erosion of the gastrointestinal (GI) tract were noted in groups fed 0.5% to 5.0% red pepper. The results of 9-and 12-month extension of this study showed normal large intestines and kidneys. In rabbits fed Capsicum Annuum Powder at 5 mg/kg day-1 in the diet daily for 12 months damage to the liver and spleen was noted. A rabbit skin irritation test of Capsicum Annuum Fruit Extract at concentrations ranging from 0.1% to 1.0% produced no irritation, but Capsicum Frutescens Fruit Extract induced concentration-dependent (at 25 to 500 microg/ml) cytotoxicity in a human buccal mucosa fibroblast cell line. An ethanol extract of red chili was mutagenic in Salmonella typhimurium TA98, but not in TA100, or in Escherichia coli. Other genotoxicity assays gave a similar pattern of mixed results. Adenocarcinoma of the abdomen was observed in 7/20 mice fed 100 mg red chilies per day for 12 months; no tumors were seen in control animals. Neoplastic changes in the liver and intestinal tumors were observed in rats fed red chili powder at 80 mg/kg day-1 for 30 days, intestinal and colon tumors were seen in rats fed red chili powder and 1,2-dimethyl hydrazine, but no tumors were observed in controls. In another study in rats, however, red chile pepper in the diet at the same dose decreased the number of tumors seen with 1,2-dimethylhydrazine. Other feeding studies evaluated the effect of red chili peppers on the incidence of stomach tumors produced by N-methyl-N'-nitro-N-nitrosoguanidine, finding that red pepper had a promoting effect. Capsicum Frutescens Fruit Extract promoted the carcinogenic effect of methyl(acetoxymethyl)nitrosamine (carcinogen) or benzene hexachloride (hepatocarcinogen) in inbred male and female Balb/c mice dosed orally (tongue application). Clinical findings include symptoms of cough, sneezing, and runny nose in chili factory workers. Human respiratory responses to Capsicum Oleoresin spray include burning of the throat, wheezing, dry cough, shortness of breath, gagging, gasping, inability to breathe or speak, and, rarely, cyanosis, apnea, and respiratory arrest. A trade name mixture containing 1% to 5% Capsicum Frutescens Fruit Extract induced very slight erythema in 1 of 10 volunteers patch tested for 48 h. Capsicum Frutescens Fruit Extract at 0.025% in a repeated-insult patch test using 103 subjects resulted in no clinically meaningful irritation or allergic contact dermatitis. One epidemiological study indicated that chili pepper consumption may be a strong risk factor for gastric cancer in populations with high intakes of chili pepper; however, other studies did not find this association. Capsaicin functions as an external analgesic, a fragrance ingredient, and as a skin-conditioning agent--miscellaneous in cosmetic products, but is not in current use. Capsaicin is not generally recognized as safe and effective by the U.S. Food and Drug Administration for fever blister and cold sore treatment, but is considered to be safe and effective as an external analgesic counterirritant. Ingested Capsaicin is rapidly absorbed from the stomach and small intestine in animal studies. Subcutaneous injection of Capsaicin in rats resulted in a rise in the blood concentration, reaching a maximum at 5 h; the highest tissue concentrations were in the kidney and lowest in the liver. In vitro percutaneous absorption of Capsaicin has been demonstrated in human, rat, mouse, rabbit, and pig skin. Enhancement of the skin permeation of naproxen (nonsteroidal anti-inflammatory agent) in the presence of Capsaicin has also been demonstrated. Pharmacological and physiological studies demonstrated that Capsaicin, which contains a vanillyl moiety, produces its sensory effects by activating a Ca2 +-permeable ion channel on sensory neurons. Capsaicin is a known activator of vanilloid receptor 1. Capsaicin-induced stimulation of prostaglandin biosynthesis has been shown using bull seminal vesicles and rheumatoid arthritis synoviocytes. Capsaicin inhibits protein synthesis in Vero kidney cells and human neuroblastoma SHSY-5Y cells in vitro, and inhibits growth of E. coli, Pseudomonas solanacearum, and Bacillus subtilis bacterial cultures, but not Saccharomyces cerevisiae. Oral LD50 values as low as 161.2 mg/kg (rats) and 118.8 mg/kg (mice) have been reported for Capsaicin in acute oral toxicity studies, with hemorrhage of the gastric fundus observed in some of the animals that died. Intravenous, intraperitoneal, and subcutaneous LD50 values were lower. In subchronic oral toxicity studies using mice, Capsaicin produced statistically significant differences in the growth rate and liver/body weight increases. Capsaicin is an ocular irritant in mice, rats, and rabbits. Dose-related edema was observed in animals receiving Capsaicin injections into the hindpaw (rats) or application to the ear (mice). In guinea pigs, dinitrochlorobenzene contact dermatitis was enhanced in the presence of Capsaicin, injected subcutaneously, whereas dermal application inhibited sensitization in mice. Immune system effects have been observed in neonatal rats injected subcutaneously with Capsaicin. Capsaicin produced mixed results in S. typhimurium micronucleus and sister-chromatid exchange genotoxicity assays. Positive results for Capsaicin were reported in DNA damage assays. Carcinogenic, cocarcinogenic, anticarcinogenic, antitumorigenic, tumor promotion, and anti-tumor promotion effects of Capsaicin have been reported in animal studies. Except for a significant reduction in crown-rump length in day 18 rats injected subcutaneously with Capsaicin (50 mg/kg) on gestation days 14, 16, 18, or 20, no reproductive or developmental toxicity was noted. In pregnant mice dosed subcutaneously with Capsaicin, depletion of substance P in the spinal cord and peripheral nerves of pregnant females and fetuses was noted. In clinical tests, nerve degeneration of intracutaneous nerve fibers and a decrease in pain sensation induced by heat and mechanical stimuli were evident in subjects injected intradermally with Capsaicin. An increase in mean inspiratory flow was reported for eight normal subjects who inhaled nebulized 10(-7) M Capsaicin. The results of provocative and predictive tests involving human subjects indicated that Capsaicin is a skin irritant. Overall, studies suggested that these ingredients can be irritating at low concentrations. Although the genotoxicity, carcinogenicity, and tumor promotion potential of Capsaicin have been demonstrated, so have opposite effects. Skin irritation and other tumor-promoting effects of Capsaicin appear to be mediated through interaction with the same vanilloid receptor. Given this mechanism of action and the observation that many tumor promoters are irritating to the skin, the Panel considered it likely that a potent tumor promoter may also be a moderate to severe skin irritant. Thus, a limitation on Capsaicin content that would significantly reduce its skin irritation potential is expected to, in effect, lessen any concerns relating to tumor promotion potential. Because Capsaicin enhanced the penetration of an anti-inflammatory agent through human skin, the Panel recommends that care should be exercised in using ingredients that contain Capsaicin in cosmetic products. The Panel advised industry that the total polychlorinated biphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and agreed on the following limitations for other impurities: arsenic (3 mg/kg max), heavy metals (0.002% max), and lead (5 mg/kg max). Industry was also advised that aflatoxin should not be present in these ingredients (the Panel adopted < or =15 ppb as corresponding to "negative" aflatoxin content), and that ingredients derived from Capsicum annuum and Capsicum Frutescens Plant species should not be used in products where N-nitroso compounds may be formed. (ABSTRACT TRUNCATED)
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PMID:Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin. 1736 37


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